Gallium is a group IIIa semi-metallic element that has been used for many years for diagnosing neoplasms and inflammation in the field of nuclear medicine. Gallium has also shown some efficacy in the treatment of cancers (Adamson et al., 1975, Cancer Chemothe. Rept 59:599-610; Foster et al., 1986, Cancer Treat Rep 70:1311-1319; Chitambar et al., 1997, Am J Clin Oncol 20:173-178), symptomatic cancer-related hypercalcemia (Warrell et al., 1989, in “Gallium in the treatment of hypercalcemia and bone metastasis”, Important Advances in Oncology, pp. 205-220, J.B. Lippincott, Philadelphia; Bockman et al., 1994, Semin Arthritis Rheum 23:268-269), bone resorption (Warrell et al., 1984, J Clin Invest 73:1487-1490; Warrell et al., 1989, supra), autoimmune diseases and allograft rejection (Matkovic et al., 1991, Curr Ther Res 50:255-267: Whitacre et al., 1992, J Newuro immunol 39:175-182: Orosz C. G. et al., 1996, Transplantation 61:783-791: Lobanoff M. C. et al., 1997, Exp Eye Res 65:797-801), stimulating wound healing and tissue repair (Bockman et al., U.S. Pat. No. 5,556,645; Bockman et al., U.S. Pat. No. 6,287,606) and certain infections, such as syphilis (Levaditi C. et al., 1931, C R Hebd Seances Acad Sci Ser D Sci Nat 192:1142-1143), intracellular bacterial infections, such as tuberculosis, histoplasmosis, and leishmaniasis (Olakanmi et al., 1997, J. Invest. Med. 45:234A: Schlesinger et al., U.S. Pat. No. 6,203,822; Bernstein, et al., International Patent Application Publication No. WO 03/053347), Pseudomonas aeruginosa infection (Schlesinger et al., U.S. Pat. No. 6,203,822), and trypanosomiasis (Levaditi C. et al. supra).
Although the exact mechanism of gallium's activity against bone resorption and hypercarcemia is not well known, its antiproliferative properties against cancer cells and antimicrobial activities are said to be likely due to its competition with ferric iron (i.e., Fe3+) for uptake by cancer cells or microorganisms (Bernstein, 1998, Pharmacol Reviews 50(4):665-682). Iron is an essential element for most living organisms, including many pathogens, and is required for DNA synthesis and various oxidation-reduction reactions (Byers et al., 1998, Metal Ions Bio syst 35:37-66; Guerinot et al., 1994, Annu Rev Microbiol 48:743-772; Howard, 1999, Clin Micobiol Reviews 12(3):394-404). Ga3+ is known to have solution- and coordination-chemistries similar to those of Fe3+ (Shannon, 1976, Acta Crystallographica A32:751-767; Huheey et al., 1993, In Inorganic Chemistry: Principles of Structure and Reactivity I, ed. 4, Harper Collins, NY: Hancock et al., 1980, In Org Chem 19:2709-2714) and behaves very similarly to Fe3+ in vivo by binding to the iron-transport protein transferrin (Clausen et al., 1974, Cancer Res 34:1931-1937: Vallabhajosula et al., 1980, J Nucl Med 21:650-656). It is speculated that gallium enters microorganisms via their iron transport mechanisms and interferes with their DNA and protein synthesis.
U.S. Pat. No. 6,203,822 and International Patent Application No. WO 03/053347 disclose methods for treating patients infected with intracellular bacteria, in particular, species of the genus Mycobacterium, by intravenously or orally administering gallium compounds to patients infected by this class of bacteria (also see Olakanmi et al., 2000, Infection and Immunity 68(10):5619-5627). These organisms primarily infect macrophages, which are known to store large amounts of iron and overexpress transferrin receptors. Parenterally or orally administered gallium compounds are easily taken up by the macrophages through transferrin receptors and then, within the cells, are taken up by the infecting organisms, thereby interfering with the organisms' metabolism. The antimicrobial activities of gallium against microorganisms other than intracellular organisms have thus far not been explored to a great extent.